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Magnesium Research

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The role of magnesium in type 2 diabetes: A brief based-clinical review Volume 24, numéro 4, December 2011

mrh.2011.0299

Auteur(s) : Martha Rodríguez-Morán1, Luis E. Simental Mendía1, Graciela Zambrano Galván1,2, Fernando Guerrero-Romero1 guerrero_romero@hotmail.com

1 Biomedical Research Unit, Mexican Social Security Institute, Predio Canoas 100, Col. Los Angeles, 34067 Durango, Dgo. Mexico;

2 Faculty of Medicine and Nutrition, University of Durango, Av. Universidad and Fanny Anitua s/n, 34000 Durango, Dgo. Mexico

Correspondence. Fernando Guerrero-Romero, MD, PhD, Siqueiros 225 esq/Castañeda, 34000, Durango, Dgo., Mexico

Introduction

Although hypomagnesemia is a common feature in patients with type 2 diabetes (T2D), the hypomagnesemia also has been proposed as a risk factor of developing T2D.

Magnesium, the most abundant intracellular divalent cation [1, 2], is involved as an essential cofactor in the enzymatic process of high-energy phosphate, energetic metabolism [3, 4], and glucose metabolic pathways [4-7]. Furthermore, clinical studies show that serum magnesium concentration is inversely associated with serum levels of C reactive protein (CRP) [8, 9], suggesting that hypomagnesemia is related with the triggering of low-grade chronic inflammatory syndrome, which is associated with the decrease of insulin sensitivity [10-17]. So, through impairment of enzymatic pathways involved in glucose transport and phosphorylation as well as by the triggering of low-grade chronic inflammation, magnesium deficiency is implicated in the decrease of insulin action [18].

In addition, it has been reported that among individuals with serum magnesium deficiency, the decrease in insulin sensitivity is not appropriately compensated by the increase of beta-cell function [19, 20] and, that oral magnesium supplementation improves the ability of pancreatic β-cells to compensate the decreases in insulin sensitivity in non-diabetic subjects with significant hypomagnesemia [21]. These data strongly suggests that magnesium deficiency also is implicated in the decrease of insulin secretion.

Given that normal glucose tolerance is maintained by the balance between insulin secretion and insulin action, it is rationale to state that hypomagnesemia could play an important role in the development of glucose metabolic disorders and T2D.

In this article we searched (in the electronic databases of medline, embase, and the Cochrane Controlled Trials Register up to June 2011) the evidence derived from epidemiological studies and clinical trials, about the relationship between magnesium and type 2 diabetes.

The Based-population studies that tested the role of magnesium dietary intake were criteria for identifying the epidemiological studies; on the other hand, the randomized-controlled clinical trials using inorganic or organic magnesium salts, with duration of at least 12 weeks, were criteria for identifying the clinical trials.

Epidemiological studies

Magnesium is an important component of unprocessed foods such as whole grains, nuts, and green leafy vegetables; however the adoption of westernized diets has contributed to the reduction of magnesium intake in the vast majority of countries. On this regards, epidemiological studies have measured the association between magnesium intake and the risk of developing T2D.

Involving a total of 394,877 individuals enrolled in 9 follow-up studies (with 366,502 subjects and mean follow-up of 10.3 years), 7 cross-sectional studies (with 28,040 individuals), and 1 interventional life study (with 335 individuals), the role of magnesium intake in the customary diet, on glucose metabolism disorders and T2D has been tested in different age, sex, and ethnicity [9, 11, 16, 17, 22-34] (table 1).

Table 1 Epidemiological studies.

Author Design N Population Conclusions
Song et al. [9] Cross-sectional 657 Nurses’ Health Study cohort Magnesium intake from diet is modestly and inversely associated with some but not all markers of systematic inflammation and endothelial dysfunction
Kim et al. [11] 20-y follow-up study 4,497 Non-diabetic Americans Magnesium intake was inversely associated with incidence of diabetes in young American adults
Kao et al. [16] 6-y follow-up cohort of nondiabetic adults 12,128 Atherosclerosis Risk in Communities Study Low dietary magnesium intake does not confer risk for type 2 diabetes
Rumawas et al. [17] Cross-sectional 2,708 Framingham Offspring cohort Improved insulin sensitivity may be one mechanism by which higher dietary magnesium intake may reduce the risk of developing type 2 diabetes.
Ma et al. [22] Cross-sectional 15,248 Atherosclerosis Risk in Communities Low serum and dietary Magnesium may be related to the etiologies of diabetes.
Bo et al. [23] Lifestyle intervention trial 335 Dysmetabolic adults Magnesium intake might play an independent role in ameliorating some metabolic, inflammatory, and oxidative markers
Hopping et al. [24] 14-y follow-up Multiethnic Cohort 75,512 Caucasian, Japanese American, and Native Hawaiian Protection against diabetes can be achieved through food choices.
Shi et al. [25] Cross-sectional 2,849 General population from Jiangsu Province of China Magnesium:iron intake ratio is an independent risk marker for diabetes
McKeown et al. [26] Cross-sectional 535 Elderly adults from USA Magnesium intake is inversely associated with prevalence of the MS in older adults
Ma et al. [27] Cross-sectional 1,036 Insulin Resistance Atherosclerosis Study Magnesium and calcium intake specifically is associated with insulin sensitivity
Lopez-Ridaura et al. [28] 18-y follow-up in women and 12-y in men 127,932 Women and men from US Significant inverse association between magnesium intake and diabetes risk
He et al. [29] 15-y follow-up study 4,637 Young Americans Young adults with higher magnesium intake have lower risk of development of metabolic syndrome
Kirii et al. [30] 5-y follow-up study 17,592 Japanese individuals Dietary intake of magnesium is associated with a reduced risk of type 2 diabetes in Japanese populations
Schulze et al. [31] Prospective study and Review from 8 cohort studies 25,067 General European population Higher cereal fiber and magnesium intakes may decrease diabetes risk.
Nanri et al. [32] 5-y Follow-up study 59, 791 Japan Public Health Center-based Prospective Study Although a small effect cannot be excluded in men, magnesium intake may not be appreciably associated with risk of type II diabetes for Japanese adults
King et al. [33] Cross-sectional 5,007 National Health and Nutrition Examination Survey Children with intakes below the RDA are more likely to have elevated CRP levels
Song et al. [34] 5-y follow-up study 39,345 Women's Health Study cohort Protective role of higher intake of magnesium in reducing the risk of developing type 2 diabetes, especially in overweight women

Results of 15 (88.2%) of these studies consistently show that magnesium dietary intake play an independent role in ameliorating metabolic, inflammatory, and oxidative markers; benefits that have been documented in different age, sex, and ethnias [9, 11, 17, 22-31, 33, 34].

A total of 9 (52.9%) studies show that magnesium intake is positively related with reduction of the risk for developing T2D; 3 (17.6%) with the beneficial effect on inflammation and oxidative markers; 2 (11.8%) with the reduction of prevalence of metabolic syndrome; and 1 (5.9%) with the improvement on insulin sensitivity. These results strongly supports the benefits of dietary magnesium intake on blood glucose metabolic disorders and T2D (table 1).

On the other hand, 2 (11.8%) studies [16, 32] show that dietary magnesium intake is not appreciably associated neither reduction of the risk of T2D nor glucose levels and inflammation markers (table 1). These findings suggest that magnesium dietary intake by itself might be inadequate to modification the health status of subjects in high risk of developing T2D.

The discrepancy between studies could be related with additional nutrients involved in the diet, which vary according ethnicity and/or with the control of involved confounders. Furthermore, is necessary to take into account that usually epidemiological studies do not report magnesium status of participants at basal and final conditions; so, in these studies the magnesium status of participants is unknown. On this regard, is important to keep in mind that magnesium-induced changes on insulin sensitivity, insulin secretion, and glucose levels are inversely related with basal magnesium level; so, magnesium intake is likely more beneficial among individuals with magnesium deficiency.

However, on the basis that 88.2% of the analyzed studies show a beneficial effect of magnesium intake on glucose metabolism and reduction in the risk of developing T2D, it should be rationale that physicians and dietitians encourage to those individuals in high risk to the consumption of foods with elevated content of magnesium.

Clinical trials

Nonetheless the evidence from epidemiological studies showing the essential role of dietary magnesium intake on insulin-mediated glucose uptake, insulin sensitivity, and markers of chronic inflammation, randomized double blind controlled clinical trials regarding magnesium supplementation are scarce and have yielded inconsistent results.

A total of 12 randomized controlled studies that have enrolled 244 non-diabetic subjects and 345 type 2 diabetic patients have tested the efficacy of oral magnesium supplementation on insulin sensitivity and glucose levels [21, 35-45].

Five studies (41.7%) [21, 35-38], conducted in non-diabetic subjects, show a beneficial role of magnesium supplementation on insulin sensitivity; of these, one (8.3%) study shows also that magnesium supplementation improves beta-cell function to compensate for variations in insulin sensitivity in non-diabetic individuals with significant hypomagnesemia [21]. These finding suggests that magnesium supplementation plays an important role not only in the improvement of insulin sensitivity but also in the beta-cell function of non-diabetic subjects (table 2).

Table 2 Randomized double blind controlled clinical trials.

Author Magnesium salt N Population Conclusions
Guerrero-Romero et al. [21] Magnesium Chloride 106 Non-diabetic subjects Improves insulin secretion for compensates variation in insulin sensitivity
Mooren et al. [35] Magnesium aspartate 52 normomagnesemic, overweight, insulin resistant, non-diabetic subjects Improves insulin sensitivity even in normomagnesemic, overweight, non-diabetic subjects
Guerrero-Romero et al. [36] Magnesium chloride 60 Non-diabetic insulin resistant subjects Improves insulin sensitivity in hypomagnesemic subjects
Chacko et al. [37] Magnesium citrate 14 Healthy, overweight individuals Favorable effects on several metabolic pathways
Paolisso et al. [38] Magnesium pidolate 12 Elderly non-diabeteic subjects Increase insulin secretion and action. Improves glucose handling
Rodríguez-Morán et al. [39] Magnesium chloride 63 Type 2 diabetic subjects Improve insulin sensitivity and metabolic control in patients with decreased serum magnesium levels
Paolisso et al. [40] Magnesium pidolate 9* Elderly non-obese type 2 diabetic patients Improves insulin sensitivity and glucose oxidation
Purvis et al. [41] Magnesium chloride 28 Type 2 diabetic patients Little impact on biochemical parameters related to diabetes
de Lordes Lima et al. [42] Magnesium oxide 128 Type 2 diabetic patients Prolonged use of magnesium in doses that are higher than usual is needed to improve control
Johnsen et al. [43] Magnesium oxide 11* Controlled Type 2 diabetic patients No effect on diabetic control
de Valk et al. [44] Magnesium aspartate 50 Type 2 diabetic patients No effect on glycemic control or plasma lipid concentrations
Gullestad et al. [45] Magnesium citrate 56 Type 2 diabetic patients No effects on glucose and insulin

*crossover trials

Interestingly, in the study conducted by Paolisso et al. [38] it was reported that magnesium supplementation increases insulin secretion and action in elderly subjects. Because, in addition to inadequate nutrient intakes, decreased magnesium absorption, increased urinary magnesium loss, elevated frequency of chronic illnesses, and/or multiple drug use, magnesium deficiency is more common in older persons than generally suspected [46]. Thus, the finding by Paolisso et al. [38], emphasizing the improves of glucose handling in the elderly, is of particular importance in the field. Unfortunately there are not more double blind studies that evaluate the effects of magnesium supplementation in geriatric populations.

Among non-diabetic subjects, magnesium aspartate (1 study), magnesium pidolate (1 study) magnesium citrate (1 study), and magnesium chloride (2 studies) were the magnesium supplements used.

On the other hand, results from 7 (58.3%) randomized double blind controlled clinical trials conducted in T2D subjects [39-45] are controversial with three (25.0%) studies showing that magnesium supplementation improves insulin sensitivity and glucose metabolic control [39-41] and, three (25.0%) studies showing no effect on glycemic control [43-45]. Results from the last one (8.3%) study conclude that only the prolonged use of magnesium with doses higher than usual is required to improve metabolic control [42] (table 2).

The target population and magnesium salts used in these randomized controlled trials were: magnesium oxide (3 studies), magnesium chloride (2 studies), magnesium citrate (1 study), and magnesium pidolate (1 study). Unfavorable results in type 2 diabetic subjects were documented with the use of magnesium oxide, magnesium aspartate, and magnesium citrate (table 2).

The controversial results in diabetic individuals who received magnesium supplementation could be related with several powerful confounders such as magnesium status of participants, additional magnesium intake in the customary diet, bioavailability of salt used, appropriate statistical power, duration of magnesium supplementation, duration of T2D, and the presence of chronic complications of diabetes, particularly complications affecting renal and intestinal function.

Interestingly, all studies that include non-diabetic individuals consistently show a beneficial effect of magnesium supplementation on glucose levels and insulin sensitivity, finding that could be related with the lower urinary loss of magnesium, that non-diabetic subjects exhibit as compared with type 2 diabetic subjects, who usually exhibited high urinary loss of magnesium, particularly the non-controlled diabetic subjects. This statement strongly suggests that patients with T2D might require higher dose of magnesium than the required by non-diabetic individuals.

Nonetheless that the benefits of chronic administration of magnesium in subjects with T2D is controversial and remains to be adequately evaluated, the routine measure of serum magnesium in diabetic patients and subjects in the high risk groups is recommendable as well as the advice for the intake of foods rich on magnesium, and/or magnesium supplements, particularly in those individuals who show low serum magnesium levels.

Further research based on randomized controlled clinical trials that includes long-term periods of magnesium supplementation and measurements of urinary magnesium levels is required.

Conclusions

The body of evidence from epidemiological studies consistently shows a strong inverse relationship between dietary magnesium intake and the risk of developing T2D.

Randomized controlled clinical trials that evaluate the benefits of magnesium supplementation on glucose levels in the individuals with T2D are scarce and controversial.

Among non-diabetic subjects, results of randomized controlled clinical trials are scarce but consistently show a beneficial effect of magnesium supplementation on insulin sensitivity and glucose levels.

Disclosure

This work was supported by grants from the Fundación IMSS, A.C.

None of the authors declare any conflict of interest to disclose.